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Cardioprotection induced by hydrogen sulfide preconditioning involves activation of ERK and PI3K/Akt pathways

  • Cardiovascular System
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

We previously reported that hydrogen sulfide (H2S) preconditioning (SP) produces cardioprotective effects against ischemia in rat cardiac myocytes. The present study aims to elucidate the signaling mechanisms involved in SP-induced cardioprotection by investigating the role of extracellular signal regulated kinase (ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/Akt. We found that preconditioning with NaHS (a H2S donor) for three cycles significantly decreased myocardial infarct size and improved heart contractile function in the isolated rat hearts. NaHS (1–100 μM) concentration-dependently increased cell viability and percentage of rod-shaped cardiac myocytes. Blockade of ERK1/2 with PD 98059 or PI3K/Akt with LY-294002 or Akt inhibitor III during either preconditioning or ischemia periods significantly attenuated the cardioprotection of SP, suggesting that both ERK1/2 and PI3K/Akt triggered and mediated the cardioprotection of SP. Moreover, SP induced ERK1/2 and Akt phosphorylation in isolated hearts. The phosphorylation of ERK1/2 induced by SP was attenuated by either glibenclamide, an ATP-sensitive K+ channel (KATP) blocker, or chelerythrine, a specific protein kinase C (PKC) blocker. In addition, ischemic-preconditioning-induced ERK1/2 activation was reversed by inhibiting endogenous H2S production, suggesting that ERK1/2 activation induced by ischemic preconditioning was, at least partly, mediated by endogenous H2S. In conclusion, KATP/PKC/ERK1/2 and PI3K/Akt pathways contributed to SP-induced cardioprotection.

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Abbreviations

2-DOG:

2-deoxy-d-glucose

Akt-i:

Akt inhibitor III

BCA:

β-cyano-l-alanine

Che:

chelerythrine

CO:

carbon monoxide

CSE:

cystathionine γ-lyase

DMSO:

dimethyl sulphoxide

ERK:

extracellular signal regulated kinase

H2S:

hydrogen sulfide

IP:

ischemic preconditioning

JNK:

c-Jun NH2-terminal kinases

KATP :

ATP-sensitive K+ channel

LAD:

left anterior descending coronary artery

MAPK:

mitogen-activated protein kinase

MEK:

MAPK/ERK kinase, or MAP kinase kinase

Na2S2O4 :

sodium dithionite

NaHS:

sodium hydrogen sulfide

NO:

nitric oxide

PAG:

dl-propargylglycine

PI3K:

phospatidylinositol 3-kinase

PKC:

protein kinase C

SP:

NaHS preconditioning

TTC:

triphenyl tetrazolium chloride

VP:

vehicle preconditioning group

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Acknowledgments

The authors thank National University of Singapore, Office of Life Sciences (R184000074712) and National Medical Research Council grant (R184000132213) for their generous research support.

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Authors and Affiliations

  1. Cardiovascular Biology Research Group, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Yeshi Hu, Xin Chen, Ting-Ting Pan, Kay Li Neo, Shiau Wei Lee, Ester Sandar Win Khin, Philip K. Moore & Jin-Song Bian

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  1. Yeshi Hu
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Correspondence to Jin-Song Bian.

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Hu, Y., Chen, X., Pan, TT. et al. Cardioprotection induced by hydrogen sulfide preconditioning involves activation of ERK and PI3K/Akt pathways. Pflugers Arch - Eur J Physiol 455, 607–616 (2008). https://doi.org/10.1007/s00424-007-0321-4

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